Review
Open Access
Full open access to this and
thousands of other papers at
http://www.la-press.com.
Abstract: Alzheimers disease (AD) is the most common neurodegenerative disorder. Currently available therapies are symptomatic
but do not alter underlying disease progression. Immunotherapeutic approaches such as anti A peptide active vaccination trials have
had limited success to date. Intravenous immunoblobulin (IVIg) is widely used in immune-mediated neurological disorders such myasthenia gravis and Guillain-Barre syndrome. These preparations have been obtained from the pooled plasma of healthy human donors
and contain natural anti-amyloid antibodies and are well tolerated. A small pilot study of passive immunotherapy using IVIg has suggested cognitive improvement. A multicenter phase III trial is ongoing and will determine whether or not this treatment can ameliorate
cognitive deficits in mild-to-moderate AD. Here, we briefly review the pathogenic role of amyloid and tau in AD, as well as immunotherapeutic efforts to date. We also summarize what is known about naturally occurring anti-A and tau antibodies in IVIg with a view
toward explaining potential mechanisms underlying their therapeutic effects.
Keywords: Alzheimer`s, immunotherapy, conformation antibodies, tau oligomers, amyloid oligomers.
67
Kayed etal
Introduction
Immunotherapy Against A
Conformation-Specific Antibodies
Tau-Based Immunotherapy
Kayed etal
IVIg Immunotherapy
Conclusions
Disclosure
References
1. Editorial. How much is dementia care worth? The Lancet Neurology. 2010;
9:1037.
2. Selkoe DJ. Alzheimers disease: Genes, proteins, and therapy. Physiol Rev.
2001;81:74166.
3. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimers disease: progress
and problems on the road to therapeutics. Science. 2002;297:3536.
4. Roberson ED, Mucke L. 100 years and counting: prospects for defeating
Alzheimers disease. Science. 2006;314:7814.
5. Shah RS, Lee HG, Xiongwei Z, Perry G, Smith MA, Castellani RJ. Current
approaches in the treatment of Alzheimers disease. Biomed Pharmacother.
2008;62:199207.
6. Stains CI, Mondal K, Ghosh I. Molecules that target beta-amyloid. Chem
Med Chem. 2007;2:167492.
7. Klaver DW, Wilce MC, Cui H, Hung AC, Gasperini R, Foa L, etal. Is BACE1
a suitable therapeutic target for the treatment of Alzheimers disease? Current
strategies and future directions. Biol Chem. 2010;391:84959.
8. Kovacs T. Therapy of Alzheimer disease. Neuropsychopharmacol Hung.
2009;11:2733.
9. Wolfe MS. Inhibition and modulation of gamma-secretase for Alzheimers
disease. Neurotherapeutics. 2008;5:3918.
10. Wisniewski T, Boutajangout A. Vaccination as a therapeutic approach to
alzheimers disease. Mt Sinai J Med. 2010;77:1731.
11. Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration
in Alzheimers disease and related disorders. Nat Rev Neurosci. 2007;8:
66372.
12. Haroutunian V, Davies P, Vianna C, Buxbaum JD, Purohit DP. Tau protein
abnormalities associated with the progression of alzheimer disease type
dementia. Neurobiol Aging. 2007;28:17.
13. Schneider A, Mandelkow E. Tau-based treatment strategies in neurodegenerative diseases. Neurotherapeutics. 2008;5:44357.
14. Iqbal K, Liu F, Gong CX, Alonso AD, Grundke-Iqbal I. Mechanisms of
tau-induced neurodegeneration. Acta Neuropathol. 2009;118:5369.
15. Iqbal K, Grundke-Iqbal I. Tau phosphatase activity as a therapeutic target
for AD. Drug News Perspect. 1998;11:104.
16. Iqbal K, Grundke-Iqbal I. Inhibition of neurofibrillary degeneration:
a promising approach to Alzheimers disease and other tauopathies.
Curr Drug Targets. 2004;5:495502.
17. Johnson GV, Jope RS, Binder LI. Proteolysis of tau by calpain. Biochem
Biophys Res Commun. 1989;163:150511.
18. Sengupta S, Horowitz PM, Karsten SL, Jackson GR, Geschwind DH, Fu Y,
etal. Degradation of tau protein by puromycin-sensitive aminopeptidase in
vitro. Biochemistry. 2006;45:151119.
19. Trojanowski JQ, Smith AB, Huryn D, Lee VM. Microtubule-stabilising
drugs for therapy of Alzheimers disease and other neurodegenerative
disorders with axonal transport impairments. Expert Opin Pharmacother.
2005;6:6836.
20. Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, Bruce J,
et al. Microtubule-binding drugs offset tau sequestration by stabilizing
microtubules and reversing fast axonal transport deficits in a tauopathy
model. Proc Natl Acad Sci U S A. 2005;102:22731.
21. Bulic B, Pickhardt M, Schmidt B, Mandelkow EM, Waldmann H,
Mandelkow E. Development of tau aggregation inhibitors for Alzheimers
disease. Angew Chem Int Ed Engl. 2009;48:174052.
71
Kayed etal
22. Duff K, Kuret J, Congdon EE. Disaggregation of Tau as a Therapeutic
Approach to Tauopathies. Curr Alzheimer Res. 2010;7:23540.
23. Sigurdsson EM. Tau-focused immunotherapy for Alzheimers disease and
related tauopathies. Curr Alzheimer Res. 2009;6:44650.
24. Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM. Immuno
therapy targeting pathological tau conformers in a tangle mouse model
reduces brain pathology with associated functional improvements.
J Neurosci. 2007;27:911529.
25. Boimel M, Grigoriadis N, Lourbopoulos A, Haber E, Abramsky O,
Rosenmann H. Efficacy and safety of immunization with phosphorylated
tau against neurofibrillary tangles in mice. Exp Neurol. 2010;224:47285.
26. Kayed R, Jackson GR. Prefilament tau species as potential targets for immunotherapy for Alzheimer disease and related disorders. Curr Opin Immunol.
2009;21:35963.
27. Wisniewski T, Boutajangout A. Immunotherapeutic approaches for
Alzheimers disease in transgenic mouse models. Brain Struct Funct. 2010;
214:20118.
28. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, etal. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in
the PDAPP mouse. Nature. 1999;400:1737.
29. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A,
etal. Long-term effects of Abeta42 immunisation in Alzheimers disease:
follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;
372:21623.
30. Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, etal. Abeta
species removal after abeta42 immunization. J Neuropathol Exp Neurol.
2006;65:10408.
31. Weiner HL, Frenkel D. Immunology and immunotherapy of Alzheimers
disease. Nat Rev Immunol. 2006;6:40416.
32. Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, etal.
11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients
with Alzheimers disease treated with bapineuzumab: a phase 2, doubleblind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9:
36372.
33. Schenk D. Amyloid-beta immunotherapy for Alzheimers disease: the end
of the beginning. Nat Rev Neurosci. 2002;3:8248.
34. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO.
Neuropathology of human Alzheimer disease after immunization with
amyloid-beta peptide: a case report. Nat Med. 2003;9:44852.
35. Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, et al.
Consequence of Abeta immunization on the vasculature of human
Alzheimers disease brain. Brain. 2008;131:3299310.
36. Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, et al.
18-Month study of intravenous immunoglobulin for treatment of mild
Alzheimer disease. Neurobiol Aging. 2009;30:172836.
37. Weksler ME, Pawelec G, Franceschi C. Immune therapy for age-related
diseases. Trends Immunol. 2009;30:34450.
38. Dodel RC, Du Y, Depboylu C, Hampel H, Frolich L, Haag A, et al.
Intravenous immunoglobulins containing antibodies against beta-amyloid
for the treatment of Alzheimers disease. J Neurol Neurosurg Psychiatry.
2004;75:14724.
39. Woodhouse A, Dickson TC, Vickers JC. Vaccination strategies for
Alzheimers disease: A new hope? Drugs Aging. 2007;24:10719.
40. Wilcock DM, Colton CA. Anti-amyloid-beta immunotherapy in Alzheimers
disease: relevance of transgenic mouse studies to clinical trials. J Alzheimers
Dis. 2008;15:55569.
41. Brendza RP, Holtzman DM. Amyloid-beta immunotherapies in mice and
men. Alzheimer Dis Assoc Disord. 2006;20:11823.
42. Brody DL, Holtzman DM. Active and passive immunotherapy for neurodegenerative disorders. Annu Rev Neurosci. 2008;31:17593.
43. Lichtlen P, Mohajeri MH. Antibody-based approaches in Alzheimers
research: safety, pharmacokinetics, metabolism, and analytical tools.
J Neurochem. 2008;104:85974.
44. Schenk DB, Seubert P, Grundman M, Black R. A beta immunotherapy:
Lessons learned for potential treatment of Alzheimers disease. Neurodegener
Dis. 2005;2:25560.
72
73